Identification of Rare Biomarkers Leading to New Targeted Therapies in NSCLC

James P. Stevenson, MD, discusses available biomarker-driven therapies in non–small cell lung cancer, as well as rarer biomarkers under clinical investigation.

James P. Stevenson, MD

In the era of precision medicine, the quest to find actionable biomarkers and match them to targeted therapies is well underway in non—small cell lung cancer (NSCLC), explained James P. Stevenson, MD.

Outside the established EGFR and ALK alterations for which targeted treatment options are approved, rarer targets including MET, RET, BRAF, HER2, KRAS, and NTRK have led to exploration of novel agents in clinical trials.

"These newer agents, especially TKIs that target some of the other less common actionable mutations in lung cancer, are coming soon to a clinic near you," said Stevenson. "If you test for them, you may be using them in the not-too-distant future. So, remember to test and get ready for what is coming."

One example comes from results of the phase I/II LIBRETTO-001 study (NCT03157128), which reported an objective response rate (ORR) of 68% with selpercatinib (LOXO-292) for patients with RET-fusion positive NSCLC, which included a complete response rate of 2%.1 Notably, selpercatinib also demonstrated high intracranial activity for the 11 patients with central nervous system involvement, with an ORR of 91%.

Additionally, the FDA has granted a fast track designation to the investigational KRAS inhibitor AMG 510 for the treatment of patients with KRAS G12C—mutated NSCLC who have received prior treatment. The decision is based on updated phase I data, which showed that the agent elicited a 100% disease control rate at the target dose in evaluable patients with this type of disease.2,3

In an interview during the 2019 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer, Stevenson, a clinical assistant professor, Department of Medicine, Case Western Reserve University School of Medicine, and a thoracic medical oncologist and vice chairman, Department of Hematology and Medical Oncology, Cleveland Clinic, discussed available biomarker-driven therapies in NSCLC, as well as rarer biomarkers under clinical investigation.

OncLive: What are some of the better-known biomarkers in NSCLC and what agents have been developed to target them?

Stephenson: After EGFR and ALK, we have BRAF V600E mutations being the most common and actionable target right now. The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) was approved and is being used as standard fashion now [for patients with those mutations].

Beyond that, there are alterations we can test for, but don't have approved agents that target them yet. These include MET exon 14 (METex14) mutations, RET fusions, HER2 mutations, KRAS G12C mutations, and NTRK fusions.

What work is being done with these other alterations?

We have recently seen exciting data with some agents targeting METex14 mutations. At [the 2019 ASCO Annual Meeting], we heard about two drugs: capmatinib and tepotinib. Early phase II data of patients with NSCLC and METex14 mutations showed significant response rates of 60% and above [with these agents]. This puts capmatinib and tepotinib in line with some of the other targeted agents used for EGFR mutations and ALK translocations. These very exciting data earned them breakthrough designation by the FDA for patients with NSCLC who have METex14 mutations.

Also, we recently heard about the LIBRETTO-001 trial, which is looking at selpercatinib in patients with RET fusions. Again, significant, durable response rates [were reported] and are in line with other targeted agents we use.

We have heard of other agents looking at KRAS G12C mutations, for which there is a targeted agent called AMG 510. These are very early data, but we are seeing responses in the first 13 patients. This is the first time KRAS has been able to be targeted with a TKI, so it’s very exciting.

HER2 mutations have been hard to target in NSCLC. They are different than HER2 amplification and overexpression, which has been targeted for a long time in breast cancer. We heard some data at [the 2019 ASCO Annual Meeting] with a drug called pyrotinib; there is also a study with poziotinib. There are TKIs being developed to target patients with HER2 exon 20 insertions.

Let’s not forget NTRK fusions, although they are hard to find. They are the least common of these alterations, but we have two approved drugs—larotrectinib (Vitrakvi) and entrectinib (Rozlytrek)—that can be used for patients with NTRK fusions. Both drugs showed high response rates in basket trials in patients with different tumor types that had NTRK fusions. In a sense, NTRK fusions in lung cancer can be like finding a needle in the haystack, but the only way to find an alteration is to look for it. If we find an NTRK fusion, it could have a substantial benefit for the patient.

Overall, we have multiple TKIs in full development showing significant positive results in early trials. My prediction is that some of them will be making it to the clinic soon.

Are there other investigational strategies to target these biomarkers that you would like to highlight?

Combinations are being looked at since we may be able to develop TKIs of downstream effectors in signaling pathways that could then be used with an upstream TKI.

This is being done now for BRAF V600E mutations with dabrafenib and trametinib. A lot of focus will be on TKI combinations, as well as developing drugs for when resistance occurs to those frontline TKIs.

What challenges remain in testing for these biomarkers?

There are a few challenges. First is actually working with our pathologist to actually order the tests. At [Cleveland Clinic], we have a panel that has broadened over the years. We will reflexively test for new diagnoses of lung cancer, but that doesn't include all the mutations I listed before.

What is the best way to get the information we need from patients? At [Cleveland Clinic], we test a small panel initially. If it turns out to be negative, we think about a broader panel through in-house testing or a broader genomic test that might be available through a corporate partner. Still, it is not hard to envision a day where broad genomic testing through next-generation sequencing will give us the answers we need at once rather than piece by piece.

That time is coming sooner rather than later. We will reflexively get 400 to 500 gene panels that will look for common and less common mutations, fusions, and translocations.

We are dealing with patients with advanced cancers; therefore, we have a finite period of time that we can get these answers. I would like to see an accelerated timeline.

Another concern with these broader genomic tests is out-of-pocket costs to the patient and their families. We need cheaper tests and of course, we always would like to get the results more quickly so we can make treatment decisions as soon as we can.


  1. Drilon A, Oxnard G, Wirth L, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of LOXO-292 in patients with RET fusion-positive lung cancers. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract PL02.08.
  2. Amgen announces new clinical data evaluating novel investigational KRASG12C inhibitor in larger patient group at WCLC 2019 [news release]. Thousand Oaks, CA: Amgen; September 8, 2019. Accessed September 9, 2019.
  3. Govindan R, Fakih M, Price T, et al. Phase 1 study of safety, tolerability, PK and efficacy of AMG 510, a novel KRASG12C inhibitor, evaluated in NSCLC. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA02.02.